Crystalline modification of 5-fluoro-1-(tetrahydro-2-furyl) uracil and complex compounds based thereon, producing antineoplastic effect

ABSTRACT

The invention relates to a novel, heretofore unknown polymorphous modification of 5-fluoro-1-(tetrahydro-2-furyl)uracil (tegafur) having antineoplastic activity. This form is crystalline, and its characteristics it differs essentially from the modification known earlier. In particular, it has an enhanced specific activity. The new form is physically stable and may find application in medicine for treating oncological patients. New anticancer medicinal substances prepared in the form of stable molecular complexes on the basis of said new modification, in particular, crystalline complexes with 6-methyluracil, and amorphous complexes with the biologically active substances from licorice, are also described.

FIELD OF THE ART

The present invention relates to the field of oncology, particularly topolymorphous modifications of anticancer drugs and to complex compoundsproducing a synergistic antineoplastic effect. The subject of theinvention is a new physically stable crystalline modification offtorafur (INN, tegafur), namely, of5-fluoro-1-(tetrahydro-2-furyl)uracil, which has an enhancedantineoplastic activity, compared with the modifications knownheretofore, as well as new anticancer drugs based thereon, in the formof stable molecular complexes.

PRIOR ART

There is known a large number of medicinal substances and theircombinations that are the result of comprehensive investigations of andimprovements in antineoplastic substances. Chemotherapeutic substanceseffective with respect to malignant neoplasms are used in clinicalpractice. Though the results of such therapy have been improvedsubstantially in recent years, it should be noted that in many cases theefficiency remains insignificant or insufficient for attaining therequired degree of inhibiting the tumor growth and an essentialextension of the life span of patients. Furthermore, most of theantineoplastic preparations are characterized by high toxicity, and thistells negatively on the process of treatment.

Ftorafur, 5-fluoro-1-(tetrahydro-2-furyl)uracil (INN, tegafur),synthesized by S. A. Giller with coworkers (U.S. Pat. No. 1,168,391) asa precursor of 5-fluorouracil (hereinafter referred to as 5FU) is aneffective antineoplastic preparation and is widely used in treatingvarious tumors, particularly, of the gastrointestinal tract and of themammary gland.

Since tegafur is a sufficiently toxic compound, numerous attempts weremade to reduce its toxicity and/or increase its effectiveness.

Pharmacopeial tegafur (corresponding to FS 42-1182-86) is characterizedin the x-ray powder diffraction pattern by the following interplanardistances d and the relative intensity of reflections I:

d, Å I 8.917 64 7.199 13 6.102 14 5.808 69 5.388 25 4.845 43 4.677 904.522 100 4.139 13 4.085 48 4.013 24 3.949 48 3.715 17 3.620 26 3.572 753.450 86 3.248 32 3.131 84 2.907 25 2.842 17 2.798 34 2.328 17 2.308 152.171 19 1.748 71

The differential scanning calorimetry (DSC) curve of the pharmacopeialtegafur, shown in FIG. 7, displays two endothermal effects. The first,broad effect is in the range of 84.8-128.1° C.; the second, meltingeffect is in the range of 172.3-192.0° C. The UV spectrum is shown inFIG. 11.

In particular, over many years attempts have been made to modernize thevery molecule of tegafur. For instance, in Belgian Patent No. 855121there are described optically active isomers of 2′R- and 2′S-tegafurwhich is chemically a racemate. However, investigations carried out bydifferent groups of scientists (for instance, by Yasumoto M. et al., “J.Med. Chem.”, 1977, vol. 20, No. 12, 1592-1594 or by Horwitz J. P. etal., “Cancer Res.”, 1975, vol. 35, 1301-1304) showed that the biologicalactivity of both isomers is practically the same and does not differfrom the activity of the racemate. The toxicity of one or another isomerdoes not display substantial differences from the initial substanceeither.

Furthermore, four crystalline forms of tegafur were produced andinvestigated (Uchida T. et al., “Chem. Pharm. Bull.”, vol. 41, No. 9,1632-1635). After treating the initial tegafur (corresponding to JPXII), α-, β-, γ-, and δ-modifications were isolated. These crystallinemodifications differ in their x-ray powder diffraction patterns, IRspectra, and DSC curves. For producing an α-form, tegafur was dissolvedin warm acetone and allowed to crystallize at room temperature.Colorless columnar crystals were separated by filtration. Colorlessprismatic crystals of the β-form were prepared from a saturated methanolsolution by evaporating the solvent with the help of a rotaryevaporator. Crystals of the γ-form were obtained by heating the βform at130° C. for 1 hour. Crystals of the δ-form were isolated byrecrystallization from a methanol solution (very slow evaporation ofmethanol) at room temperature. None of the above-cited modificationsoffers essential therapeutic advantages.

From the above-stated a conclusion can be drawn that the problem ofenhancing the tegafur activity by the synthesis or isomers or producingpolymorphous modifications is still unsolved.

Concurrently, searches for compositions—synergistic mixtures containingtegafur as the active substance—were carried out.

The discovery of a combination of medicinal substances, consisting oftegafur and uracil, was preceded by an idea that since 5-FU becomesmetabolized too rapidly and loses activity in the organism, uracil maybe used for inhibiting these processes (U.S. Pat. No. 5,534,513). Itturned out that uracil as such does not display an antineoplasticactivity, it has the property to potentiate the antineoplastic effect.An investigation of the effectiveness of a mixture of tegafur and uracil(tegafur:uracil molar ratio of 1:4) is discussed, e.g., in the work ofKagawa Y. et al., “Cancer Investigation”, 1955, vol. 13, No. 5, 470-474.

Furthermore, there was produced and investigated a compositioncontaining tegafur, uracil and folic acid (Sanchiz F. and Milla A.,“Jpn. Journal Clin. Oncol.”, 1994, vol. 24, No. 6, 322-326).

In such combination preparations an aspect of extreme importance is anoptimal dosage of both the active component and of the substancepotentiating the activity. It is desirable that the potentiatingsubstance should be used in minimal doses (for reducing its own toxiceffect) or that this substance per se should practically have no toxiceffect. Presently known synergistic preparations containing tegafur, asthe active component, and a potentiator are not always optimized withrespect to both the qualitative and quantitative formulation of thecomponents. For instance, uracil (which is usually used for potentiatingthe activity of tegafur) is a toxic compound, though its toxicity isless pronounced compared with other substances capable of potentiatingthe action of tegafur:thymine, thymine, thymidine or uridine (Fujita H.,Experimental and Clinical Pharmacotherapy, Issue 12, Riga, 1983, p.205).

Hence, the present-day therapy of neoplasms requires improvedpreparations used in oncology, as well as developing medicinalpreparations displaying high antineoplastic activity along withminimized toxicity.

DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide physically stableform of tegafur having an enhanced pharmacological activity. As a resultof experiments it was unexpectedly found that an enhanced specificactivity along with physical stability during a long period of timesufficient for commercial use is displayed by a hitherto-unknownmetastable modification of tegafur, hereafter referred to as form V.

A novel form V comprises a light, “airy” white powder.

Form V is characterized in the x-ray powder diffraction pattern by thefollowing interplanar distances d and the relative intensity ofreflections I:

d, Å I 9.035 63 7.237 23 6.149 19 5.839 100 5.413 17 4.704 42 4.551 624.104 36 4.041 28 3.966 25 3.730 20 3.626 25 3.588 42 3.473 60 3.437 503.255 30 3.143 36 2.915 23 2.382 16 2.336 20

The carried out thermal analysis revealed in the novel form threepronounced peaks on the DSC curve.

The first peak is a transition of α→β type in the region of 96.6-102° C.The second and third peaks are a superposition of two endothermaleffects: a β→γ transition in the range of 157.1-174.2° C. and an effectof melting of the γ-form with the maximum temperature of 174° C.superposed thereonto. The point of superposition of the second and thirdeffects is in the neighborhood of 167.6° C.

The UV spectrum of form V is shown in FIG. 10.

Form V of tegafur is prepared by dissolving a pharmacopeial tegafursubstance or its individual polymorphous modifications in water,alcohol, or an alcoholic-aqueous mixture. The solvent should preferablybe preheated to 40-65° C. After that the resulting solution isintroduced into a container with an anti-solvent (e.g., dimethyl ether,diethyl ether or chloroform) preliminarily cooled down to a temperatureof at least 10° C. The resulting precipitate is separated, the residuesof the solvents are removed, and a crystalline powder of form V isobtained.

The novel crystalline modification of tegafur is physically stable anddoes not lose its properties on blending with pharmaceuticallyacceptable carriers or fillers, which makes this modification suitablefor use in medicinal preparations. However, unexpectedly it was foundthat said form V has the property of forming completes with some organicmolecules, including those having biological activity. In particular,complex compounds were obtained with2,4-dioxo-6-methyl-1,2,3,-tetrahydropyrimidine (hereafter referred to asmethyluracil) and with biologically active vegetable extracts produced,in particular from licorice (Radices Glycyrrhizae).

Complex compounds can be produced under definite technologicalconditions, leading to the formation of non-valence bonds between themolecules of tegafur and the molecules of organic compounds which enterinto the interactions of such kind with tegafur.

There are three possible ways of synthesizing complex compounds. Thefirst way envisages a single-step transfer of a physical mixture oftegafur and other organic molecules which are planned to be included inthe composition of a complex into a high-energy (metastable) state. Itwas found that under these conditions tegafur passes into form V whichis capable to form stable molecular complexes.

A physical mixture can be transferred into a high-energy state bydifferent methods, the only condition in their carrying out being thatthey should yield form V of tegafur.

Such methods can be, for example, joint micronization (particularly,milling) or other known methods affecting the energy of a molecule.

The second way of producing complexes consists in blending apreliminarily prepared form V of tegafur with other components of thecomplex: an individual compound or a mixture of compounds which at themoment of blending are in a thermodynamically stable state.

The third way of producing complexes consists in blending apreliminarily prepared form V of tegafur with the second component ofthe complex, this second component already being in the high-energystate.

For producing complexes, it is possible to use, in particular:methyluracil (M. D. Mashkovskii, Drugs, 1997, Kharkov, vol. 2, p. 168(in Russian)), β-form of methyluracil (hereafter referred to asBetamecil) having a reduced toxicity (U.S. Pat. No. 5,543,147),different licorice extracts, e.g., Extractum Glycyrrhizae siccum (M. D.Mashkovskii, Drugs, 1997, Kharkov, vol. 1, pp. 345-346 (in Russian)).

The molecular complex tegafur-methyluracil in the molar ratio of 1:2(complex compound 1a) is a white fine-crystalline powder, and it ischaracterized in the x-ray powder diffraction pattern by the followinginterplanar distances d and the relative intensity of reflections I:

d, Å I 9.090 19 7.234 32 6.883 100 5.864 13 4.831 27 4.571 13 4.197 253.627 15 3.448 18 3.254 26 3.192 13 3.149 6 2.933 13 2.448 8 2.300 8

The DSC curve of compound 1a is shown in FIG. 8. The curve displays twoendothermal effects. The first effect of α→β type is in the range of117.1-132° C. The second effect of melting of β-form is in the range of149.9-167.1° C.

The UV spectrum of compound 1a, characterizing the individuality of thissubstance, is shown in FIG. 12.

The molecular complex tegafur-methyluracil in the molar ratio of 1:1(complex compound 1b) is a white fine-crystalline powder, and it ischaracterized in the x-ray powder diffraction pattern by the followinginterplanar distances d and the relative intensity of reflections I:

d, Å I 7.187 53 6.841 100 4.806 41 4.181 37 3.669 20 3.474 21

The complex tegafur-licorice (complex compound 2) is amorphous in termsof x-ray diffraction pattern analysis and comprises a light clumpingyellow powder with a brownish hue.

The DSC curve of compound 2, shown in FIG. 9, displays e combination oftwo endothermal effects: a broad effect lies in the range of 98.2-125.0°C.; the second effect, accompanied by decomposition of the substance,lies in the range of 125.0-171.5° C.

The UV spectrum of compound 2, which supports the individuality of thissubstance, is shown in FIG. 13.

Form V excels in solubility the hitherto-known modifications of tegafur.Moreover, the novel form of tegafur, compared with the hitherto-knownpolymorphous modifications thereof, has an enhanced specific activity.Complex compounds display a still greater specific activity (comparednot only with pharmacopeial tegafur, but also with novel form V), i.e.,there takes place potentiation of the pharmacological effect.

The obtained novel crystalline modification of ftorafur and complexcompounds based on this modification may find extensive application inmedicine for treating oncological diseases. This will make it possibleto broaden the range of medicaments acting on tumor cells and,correspondingly, to increase the effectiveness of treating patientssuffering from malignant neoplasms.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows an x-ray powder diffraction pattern of the claimed form Vof tegafur;

FIG. 2 shows an x-ray powder diffraction pattern of pharmacopeialtegafur;

FIG. 3 shows an x-ray powder diffraction pattern of the molecularcomplex tegafur-methyluracil in the ratio of 1:2;

FIG. 4 shows an x-ray powder diffraction pattern of the molecularcomplex tegafur-methyluracil in the ratio of 1:1;

FIG. 5 shows an x-ray powder diffraction pattern of the complex compoundtegafur-licorice;

FIG. 6 shows a DSC curve of the claimed form V of tegafur;

FIG. 7 shows a DSC curve of pharmacopeial tegafur;

FIG. 8 shows a DSC curve of the molecular complex tegafur-methyluracilin the ratio of 1:2;

FIG. 9 shows a DSC curve of the complex compound tegafur-licorice;

FIG. 10 shows a UV spectrum of the claimed form V of U. tegafur;

FIG. 11 shows a UV spectrum of pharmacopeial tegafur;

FIG. 12 shows a UV spectrum of the molecular complextegafur-methyluracil in the ratio of 1:2;

FIG. 13 shows a UV spectrum of the complex compound tegafur-licorice;

FIG. 14 shows the results of studying the specific activity ofpharmacopeial tegafur, of form V of tegafur, of complex compound 1a, andof complex compound 2.

BEST MODE OF CARRYING OUT THE INVENTION

1. Preparing Form V of Tegafur

The crystalline modification of tegafur according to the presentinvention is prepared in the following manner.

A saturated aqueous solution of the starting component—pharmacopeialtegafur (corresponds to FS 42-1182-86)—is prepared at the temperature of45° C. 0.5 liter of the obtained solution is dispersed into a containerwith chloroform preliminarily cooled down to 2° C. The volume of thechloroform is 0.4 liter. The suspension is allowed to settle, thechloroform layer with the precipitate is separated, the precipitate isfiltered-off, the residual solvent is removed at a reduced pressure(10⁻¹ mm Hg) to obtain the target product. The yield of form V oftegafur is 62% of the starting pharmacopeial substance.

2. Preparing a Tegafur-Methyluracil Complex (1:2)

0.5 liter of a 0.1 M aqueous solution of form V of tegafur and 0.5 literof a 0.2 M aqueous solution of Betamecil are prepared at the temperatureof 100° C. The resulting solutions are carefully combined and left in athermostat at the temperature of 60° C. for 1.5 h. Then the solution iscooled down to 2° C., the precipitate is filtered-off and dried at areduced pressure (10⁻¹ mm Hg) to obtain the target product. The yield is71%.

3. Preparing a Tegafur-Methyluracil Complex (1:1)

0.5 liter of a 0.2 M aqueous solution of form V of tegafur and 0.5 literof a 0.2 M aqueous solution of methyluracil are prepared at thetemperature of 100° C. The resulting solutions are carefully combinedand left in a thermostat at the temperature of 60° C. for 3 h. Then thesolution is cooled down to 2° C., the precipitate is filtered-off anddried at a reduced pressure (10⁻¹ mm Hg) to obtain the target product.The yield is 68%.

4. Preparing a Complex of Tegafur and a Mixture of Organic Constituentsof Licorice Extract

As a ligand, dry licorice extract (Radices Glycyrrhizae) is used (S. I.Uspenskaya et al., Rossiiskii Khimicheskii Zhurnal, 1997, vol. 41, No.5, pp. 124-129). The dry extract comprises an amorphous, porous,hygroscopic powder having a characteristic color and a specific odor.During storage the powder may clump, but the clumps become easilydestroyed under shaking. The extract is readily soluble in water andgives opalescing solutions. The content of glycyrrhizic acid in drylicorice extract is 20.12%.

10 g of form V of tegafur are dissolved in 0.25 liter of water at thetemperature of 40° C. In another container 5 g of dry licorice extractare dissolved in 0.1 liter of water at the same temperature. Theresulting solutions are combined and left in a thermostat at thetemperature of 40° C. for 30 minutes. Then the solution is cooledrapidly down to 2° C., the precipitate is filtered-off and dried toobtain the target product. The yield is 75%.

The obtained novel modification of tegafur and the complex compoundsbased on said modification were investigated by x-ray powder diffractionanalysis techniques.

The x-ray powder diffraction analysis was carried out on an automatedpowder diffractometer (CuK, radiation, graphite monochromator onsecondary run; scan mode, 4 to 64 2θ; step, 0.1°; scan rate, 2°/min).The diffraction pattern of the claimed form V and of the complexes withmethyluracil displays characteristic reflections. The x-ray powderdiffraction pattern of the amorphous complex with licorice was recordedas described above, the only difference being in that, the sample beinghygroscopic, recording was carried out under a fine polymeric (Mylar)film. The x-ray powder diffraction pattern of the complex with licoricedisplays diffuse scattering (amorphous halo), typical of amorphoussubstances (Whittaker E. J. W., Crystallography, Pergamon Press, Oxford,1981) in the range of 15-30 2θ°, and a broad reflection of the filmpolymer with a center in the vicinity of 11 2θ°, superposed thereon.

The results are shown in FIGS. 1-5.

The investigations carried out with the help of differential scanningcalorimetry, shown in FIGS. 6-9, prove the novelty of the proposedmedicinal compounds. The DSC characteristics of form V differessentially from both the pharmacopeial sample of tegafur (whichcorresponds to FS 42-1182-86) and the hitherto-known polymorphousmodifications.

Thermoanalytical investigations were carried out on an STA-409thermoanalyzer (NETZSCH, Germany), which allows carrying outsimultaneous investigations by thermogravimetic techniques (TG) and bydifferential scanning calorimetry techniques (DSC). The investigationswere carried out in the atmosphere of dry helium (1 atm) with the scanrate of 10°/min. In the experiments, 7-20 mg weighed samples were placedin platinum crucibles.

The temperature corresponding to the onset of a peak on the DSC curvewas determined from the intersection of the straight line correspondingto the datum line and with the straight line which is a tangent at theinflection point of the ascending line of the peak.

To determine the sensitivity coefficients which relate the area underthe DSC curve with the thermal effect, a calibration against indium andsapphire was carried out under the conditions identical to those in theworking experiments. The integration of peaks on the DSC curves and thecalculations of thermal effects were carried out in accordance withprograms which are part of the software of the STA-409 instrument.

The UV spectra (FIGS. 10-13) were recorded on an “Aminec”spectrophotometer. Solutions with the concentration of 0.2% wereprepared in a 0.1 M phosphate buffer with pH=6.8.

INDUSTRIAL APPLICABILITY Determination of the Solubility of InvestigatedPreparations and of Tegafur

The solubility was determined in accordance with the requirements setout in the article “Solubility”, USPXXTIII (1995, p. 2071).

TABLE 1 Solubility % with Description Temperature respect to of sampleof solvent, ° C. g/ml % tegafur pharmacopeial 20 0.0080 0.8 tegafur FormV of 20 0.0150 1.5 187.5 tegafur Complex 20 0.0095 0.95 119.0 compound1a Complex 20 0.0102 1.02 127.5 compound 1b Complex 20 Solubility was —compound 2 not determined, because the preparation forms opales- cingsolutions

As is seen from the data presented in Table 1, the solubility of theclaimed preparations: of form V of tegafur, complex compound 1a and 1bis higher than the solubility of pharmacopeial tegafur, the solubilityof complex compound 2 could not be determined because of the vegetablecomponent—licorice which forms slightly turbid opalescing solutions.

Determination of Specific Activity—Cytotoxicity of Samples of ClaimedPrepatrations, Compared with Pharmacopeial Tegafur on a Culture ofUterine Neck Cancer Cells

The determination was carried out by following the known procedure(Mosmann N. T., J. Immunology Methods, 1983, vol. 65, 55-63, CarmichelJ. et al., Cancer Res., 1987, vol. 47, 936-946) on a culture of uterineneck cancer cells. The cells were grown at 37° C. on the RPMI 1640medium with additives of a 10%embryonal serum of cows and 200 u/ml ofgentamicin. CO₂ content in the incubator atmosphere was 10%. The cellswhich were in the exponential phase of growth were suspended withtrypsin and inoculated in an amount of 4×10³ into each socket of a96-socket dish for monolayer cultures. Solutions of samples of thepreparations to be investigated were prepared by dissolving 23 mg ofeach preparation in 10 ml of a culture broth, 10⁻² M solutions beingthus obtained. These were starting solutions for obtaining solutions ofa lower concentration by diluting them with the culture broth. Directlybefore adding the solutions to the cells, these solutions weresterilized by filtering through millipore filters. One day after theinoculation of the cells, solutions of samples of the preparations to beinvestigated in prescribed concentrations were added into each socket ofthe dish. After that the cells grew for another 4 days.

All in all, 9 concentrations of each of the 4 samples of theinvestigated preparations were tested.

Quantitative estimation of the cytotoxicity of the investigatedpreparations was carried out with the use of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). NTThas a selective ability for metabolizing in cell mitochondria with theformation of formasane, a colored produce which has an absorptionmaximum at the wavelength of 530-570 nm, there existing a correlationbetween the degree of the inhibition of mitochondria and the staining ofcells. 0.5 mg/ml was added into each socket of the dish 4 hours beforethe completion of cells cultivation. On completion of the incubation,the culture broth was removed from the dish sockets, the formasanecrystals were dissolved, and the cells were scanned on an automaticMultiscan MCC/340P reader at the 540 nm wavelength. The results werecalculated in percent of the cells subjected to the effect of theinvestigated preparations, absorbed at 540 nm, as against the absorptionof control cells.

The action of each concentration of the investigated preparations oncancer cells was estimated from the results of 4-6 independentexperiments, treated by methods of mathematical statistics. The dataobtained in the investigations are presented in Table 2 and in FIG. 14.

TABLE 2 Optical density at 540 nm Concentration Complex Complex ofpreparations, compound compound M Pharma- 1a (tegafur (tegafur (onconversion copeial Form V of and methyl- and to tegafur) tegafur tegafururacil) licorice) 1 2 3 4 5 10⁻⁶ 0.76 ± 0.05 0.79 ± 0.08 0.45 ± 0.040.64 ± 0.04 5 × 10⁻⁶ 0.76 ± 0.08 0.73 ± 0.03 0.53 ± 0.−3 0.96 ± 0.0910⁻⁵ 0.81 ± 0.09 0.73 ± 0.08 0.38 ± 0.04 — 5 × 10⁻⁵ 0.80 ± 0.10 0.70 ±0.03 0.35 ± 0.06 0.54 ± 0.08 10⁻⁴ 0.81 ± 0.13 0.56 ± 0.06 0.74 ± 0.120.45 ± 0.03 5 × 10⁻⁴ 0.56 ± 0.12 0.44 ± 0.05 0.37 ± 0.05 0.30 ± 0.0510⁻³ 0.45 ± 0.06 0.35 ± 0.02 0.32 ± 0.05 0.33 ± 0.06 5 × 10⁻³ 0.28 ±0.005 0.25 ± 0.02 0.16 ± 0.01 0.32 ± 0.005 10⁻² 0.26 ± 0.04 0.16 ± 0.010.06 ± 0.03 0.04 ± 0.005

As is seen from the data of Table 2 and from the plot presented in FIG.14, all the investigated preparations produce different cytotoxic effecton cancer cells. However, the claimed preparations, namely, form V oftegafur, and also complex compounds 1a and 2 excel tegafur essentiallyin the effect on the proliferation of cancer cells. For instance,tegafur in the range of concentrations of 10⁻⁶-10⁴ M does not affect theproliferation of cancer cells. Form V of tegafur inhibits theproliferation of cells at the concentration of 5×10⁻⁵ M; at theconcentration of 10⁻⁴ M the preparation inhibits the proliferation by70% more intensively than tegafur does. Complex compound 1a(tegafur-methyluracil) produces inhibiting is effect on theproliferation of cells already starting with the concentration of 10⁻⁶M; the same applies to complex compound 2 (tegafur-licorice). It shouldbe taken into account that in complex compound 1a form V of tegafur ispresent in a ½ smaller amount, and in compound 2 in a ⅓ smaller amount.Hence, a clearly pronounced cytotoxic effect is observed in this case.

What is claimed is:
 1. A crystalline modification of5-fluoro-1-(tetrahydro-2-furyl)uracil, characterized in the x-ray powderdiffraction pattern by the following interplanar distances d and therelative intensity of reflections I: d, Å I 9.035 63 7.237 23 6.149 195.839 100 5.413 17 4.704 42 4.551 62 4.104 36 4.041 28 3.966 25 3.730 203.626 25 3.588 42 3.473 60 3.437 50 3.255 30 3.143 36 2.915 23 2.382 162.336 20


2. A complex compound formed by neutral organic molecules of medicinalsubstances consisting essentially of5-fluoro-1-(tetrahydro-2-furyl)uracil and licorice (RadicesGlycyrrhizae).
 3. A complex compound formed by neutral organic moleculesof medicinal substances, consisting essentially of5-fluoro-1-(tetrahydro-2-furyl)uracil and2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine.
 4. A complex compoundaccording to claim 3, wherein2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimide is Betamecil.
 5. A complexcompound according to claim 3, wherein the5-fluoro-1-(tetrahydro-2-furyl)uracil and2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine are present in a 1:2molar ratio respectively.
 6. A complex compound according to claim 5,wherein the x-ray powder diffraction pattern is characterized by thefollowing interplanar distances d and the relative intensity ofreflections I: d, Å I 9.090 19 7.234 32 6.883 100 5.864 13 4.831 274.571 13 4.197 25 3.627 15 3.448 18 3.254 26 3.192 13 3.149 6 2.933 132.448 8 2.300
 8.


7. A complex compound according to claim 3, wherein the medicinalsubstances are present in a 1:1 molar ratio, respectively.
 8. A complexcompound according to claim 7, wherein the x-ray powder diffractionpattern is characterized by the following interplanar distances d andthe relative intensity of the reflections I: d, Å I 7.187 53 6.841 1004.806 41 4.181 37 3.669 20 3.474
 21.


9. A complex compound formed by neutral organic molecules of medicinalsubstances, the medicinal substances consisting essentially of5-fluoro-1-(tetrahydro-2-furyl)uracil and licorice (RadicesGlycyrrhizae) in a weight ratio of 1:1 to 4:1.
 10. A complex compoundaccording to claim 9, wherein the 5-fluoro-1-(tetrahydro-2-furyl)uraciland the licorice are present in a weight ratio of 2:1, respectively. 11.A complex compound according to claim 10, wherein the clearly pronouncedreflections typical of crystalline forms are absent in the x-ray powderdiffraction pattern.
 12. A complex compound formed by neutral organicmolecules of medicinal substances, the medicinal substances consistingessentially of 5-fluoro-1-(tetrahydro-2-furyl)uracil and2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine and the5-fluoro-1-(tetrahydro-2-furyl)uracil is a crystalline modificationcharacterized by an x-ray powder diffraction having the followinginterplanar distances d and the relative intensity of reflections I: d,Å I 9.035 63 7.237 23 6.149 19 5.839 100 5.413 17 4.704 42 4.551 624.104 36 4.041 28 3.966 25 3.730 20 3.626 25 3.588 42 3.473 60 3.437 503.255 30 3.143 36 2.915 23 2.382 16 2.336 20


13. A complex compound according to claim 12, wherein the medicinalsubstances are present in a 1:2 molar ratio, respectively.
 14. A complexcompound according to claim 4, wherein the medicinal